Chemical constituents derived from Artocarpus xanthocarpus as inhibitors of melanin biosynthesis Yu-Jing Jin a,1 , Cha-Chi Lin b,1 , Tzy-Ming Lu c , Jih-Heng Li b , Ih-Sheng Chen b,d,e , Yueh-Hsiung Kuo f,g , Horng-Huey Ko a,e,⇑ a Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan b School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan c Department of Pharmacy, Tajen University, Pingtung County 907, Taiwan d Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan e Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan f Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan g Department of Biotechnology, Asia University, Taichung 413, Taiwan article info Article history: Received 1 February 2015 Received in revised form 5 July 2015 Accepted 9 July 2015 Keywords: Chinese herb Artocarpus xanthocarpus Moraceae Oligomer of stilbene Hexahydrochrysene Tyrosinase Melanin abstract Twenty-four compounds, including the previously unknown artoxanthocarpuone A, artoxanthocarpuone B, hydroxylakoochin A, methoxylakoochin A, epoxylakoochin A, and artoxanthol, were isolated and char- acterized spectroscopically. Among them, artoxanthol is stilbene oligomer presumably constructed in a 5,11,12-triphenyl hexahydrochrysene scaffold by a Diels–Alder type of reaction, for which a biosynthetic pathway is proposed. Artoxanthol, alboctalol, steppogenin, norartocarpetin, resveratrol, oxyresveratrol, and chlorophorin potently inhibited mushroom tyrosinase activity with IC 50 values from 0.9 to 5.7 lM that were all far stronger than the positive controls. Artoxanthocarpuone A, artoxanthocarpuone B, methoxylakoochin A, lakoochin A, cudraflavone C, artonin A, resveratrol, and chlorophorin reduced tyrosinase activity and inhibited a-melanocyte-stimulating hormone-induced melanin production in B16F10 melanoma cells without affecting cell proliferation. Collectively, the results suggest that the constituents of Artocarpus xanthocarpus have potential to be used as depigmentation agents. Ó 2015 Elsevier Ltd. All rights reserved. 1. Introduction The Artocarpus genus includes monoecious evergreen trees and shrubs capable of producing milky sap and is among the most important genera within the Moraceae family, which are widely distributed in tropical Asia, Polynesia, and the Pacific Islands (Liao, 1996). A number of pharmacologically active constituents have been isolated from Artocarpus species in recent decades, with these having diverse activities including antioxidant, anti-melano- genesis, antimicrobial, anti-arthritic, anti-inflammatory, antiplate- let aggregation, cytotoxic, antityrosinase, and anti-5a-reductase activities (Botta et al., 2005; Hakim et al., 2006; Jagtap and Bapat, 2010; Lan et al., 2013). This success has spurred the contin- ued search for more bioactive constituents of Formosan Artocarpus medicinal plants. Artocarpus xanthocarpus Merr. (Moraceae) is a small tree that grows in the Philippines, Borneo, and Lanyu Island of southeast Taiwan. Lumber from A. xanthocarpus is often used in Lanyu for construction, furniture, or boats (Liao, 1996). To date, the only bioactive compound isolated from A. xanthocarpus is artoxanthochromane, which has antityrosinase and free radical- scavenging activities (Ko et al., 2013). Given the promise of other Artocarpus species, an investigation was carried out to search for additional valuable bioactives from A. xanthocarpus roots. In humans, solar ultraviolet (UV) radiation, oxidative stress, chronic inflammation, and the excessive release of a-melanocyte- stimulating hormone (a-MSH) can trigger melanin biosynthesis and lead to hyperpigmentation (Jeong et al., 2009; Kim and Yokozawa, 2009; Lee et al., 2010a). Common manifestations of skin hyperpigmentation include freckles, melasma, solar lentigines, age spots, and post-inflammatory hyperpigmentation, all of which can be serious aesthetic concerns. One of the rate-limiting steps of melanin biosynthesis is catalyzed by the enzyme tyrosinase, which is a copper-containing polyphenol oxidase and is widely distributed in plants and in animals (Arung et al., 2007; Donsing et al., 2008). This enzyme catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA) and O-dopaquinone via hydroxylation and oxidation reactions, respectively (Parvez http://dx.doi.org/10.1016/j.phytochem.2015.07.003 0031-9422/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan. E-mail address: hhko@kmu.edu.tw (H.-H. Ko). 1 These authors contributed equally to this work. Phytochemistry 117 (2015) 424–435 Contents lists available at ScienceDirect Phytochemistry journal homepage: www.elsevier.com/locate/phytochem